Chikungunya fever (CHIK) is a highly important arbovirosis currently established in Latin America and the Caribbean (LAC); its acute and chronic burden is an overlooked issue for policy makers. Disease spread control and proper management of chronic-derived sequelae do not seem like a realistic goal in short- and mid-term. The CHIKV circulating in the Western Hemisphere is closely related to strains from Philippines, China, and Yap (Federated States of Micronesia), and vertical and horizontal transmission of infection has been reported. Pathogenesis is still not well understood, and vaccines are under development yet. Here, we provide a summary of information regarding LAC spread of the disease from a public health, clinical and molecular perspective, particularly from the experience in Colombia.
- Latin America
- public health
- molecular epidemiology
- clinical manifestations
Chikungunya fever (CHIK) is a highly important arbovirosis to Latin America and the Caribbean (LAC) because it is an infectious disease that have evolved from a simple threat to an established disease with acute and chronic burden to almost all the American continent, both mainland and overseas territories. Moreover, the presence of suitable ecological conditions in nontropical areas and our highly interconnected world have led to the report of cases in at least four continents in the world. CHIK is an arthritogenic fever that has arrived to stay in the Americas. After its introduction in 2013 to the island of Saint-Marteen (two autochthonous cases confirmed on December 6, 2013), it quickly spread through overseas Caribbean territories with autochthonous transmission (Martinique and Saint Marteen, December 19, 2013; Guadeloupe, December 24, 2013; Saint Berthelemy, December 31, 2013; and British Virgin Islands, January 15, 2014). Next, on February 21, the World Health Organization (WHO) confirmed the arriving of CHIK to mainland South America in French Guiana with seven confirmed cases (two autochthonous). Since then, the disease has spread over the entire continent. Until today, it continues accounting for important acute and chronic burden to the healthcare systems of the region [1–7]. For example, in Colombia, until June 2016, more than 16,000 new cases of CHIK have been reported.
Currently, almost every country in LAC has reported autochthonous transmission of CHIK, some of them in confined territories, but others such as Colombia, Venezuela, and Ecuador with a more generalized and intense disease transmission. Non-LAC territories have suffered the impact of travel and suitable ecological conditions with vector availability (
As showed, CHIKV can easily be spread into areas where suitable ecological conditions are done. In 2016, 16,653 CHIK cases in LAC have been newly diagnosed, both suspected and confirmed (epidemiological week 7) . By the same time, in 2014, there were 1980 cases, but the current data are only about 17% of the reported cases in the same epidemiological week in 2015. Although it is possible that CHIK cases this year would be importantly lower than the previous, attention must be paid because probably it is going to have an epidemiological behavior that resembles dengue with episodes of seasonal epidemic outbreaks. Moreover, after the arriving of Zika to the region, efforts must be oriented not only to vector control programs but to develop proper diagnosis, treatment, and follow-up strategies in order to grant management and assessment of acute and chronic symptoms. Chikungunya, dengue, and Zika are three arbovirosis that already pose an important burden to LAC healthcare systems. They have showed our weaknesses in managing infectious disease spread and taught us that viral emerging infectious diseases are more than febrile illnesses. The latent threat of introduction of other
2. Virology and molecular epidemiology
CHIKV is a member of the genus
The CHIKV is an enveloped, spherical virus with a diameter of 60–70 nm. It has a RNA, positive sense, linear genome of 11.8 kb that resembles eukaryotic mRNAs; given that at the 5′ end, it has a methyl guanylate cap, which is a nonstructural poly-protein precursor, and at the 3′ end, it has a poly(A) tail . The 5′ precursor is cleaved into nsP1, nsP2, nsP3, and nsP4, which are involved in the virus replication and have functions and structures that are shared by other alphaviruses [17,19–21]. The nsP1 protein functions as cytoplasmic RNA capping enzyme, the nsP2 protein is a cysteine protease with a partially constricted substrate-binding site and two separate domains with helicase and protease activity , the nsP3 protein is essential for negative strand RNA synthesis, and the nsP4 protein works as an RNA-dependent RNA polymerase [17–19,21]. The 3′ poly(A) tail consists of 26S mRNA whose products include the structural proteins: the surface glycoproteins (E1 and E2), the capsid protein, and small peptides (E3 and 6K). The surface glycoprotein E2 has a role in viral attachment, and the surface glycoprotein E1 is the fusion protein that facilitates the viral entry [18,19,22].
Currently, there are three CHIKV-identified genotypes based on the E1 gene and the full genome sequence: East/Central/South African (ECSA), West African, and Asian. Phylogenetic analyses suggest that CHIKV spread from Africa to Asia episodically [23,24] and that the CHIKV strains circulating in the Caribbean came from the >2005 Southeast Asian clade, which previously moved into Western and South Pacific (American Samoa and Yap) and then to the Western Hemisphere. The CHIKV circulating in the Western Hemisphere is closely related to strains from Philippines, China, and Yap (Federated States of Micronesia) [25–30]. By contrast, the circulation of the ECSA genotype has been confirmed in Brazil apparently imported from Angola . During the current LAC epidemics, the virus has showed mutation rates that are in accordance with previous evolutionary rate model, which predicted approximately 10 nucleotide mutations over the entire genome during the course of a 1-year epidemic [23,26,30]. The LAC CHIKV possess two unique amino acid differences and a 12-nucleotide deletion that could be useful in future for tracking of this strain .
3. Pathogenesis and disease transmission
Conventionally, CHIKV transmission is considered to be through flying arthropods of the
After its entry to the human host, the CHIKV first replicates in the skin fibroblasts [38,39], next it enters to the circulatory system, and triggers an early type I interferon response . Apparently, alterations in this response are associated with more severe disease and death . Next, it disseminates from blood to various tissues, it lodges in immune-privileged niches, and it replicates in the joints and skeletal muscles that are associated with extensive inflammatory cell recruitment [38,40,42–45]. CHIKV infection can persist in mononuclear cells and macrophages that are another primary cellular target and help in virus dissemination and chronic articular symptoms [38,46,47]. It has been proposed that viral persistence is associated with expression of interferon (IFN)-α, interleukin (IL)-10, and monocyte chemotactic protein 1 (MCP-1 or CCL2) . Chikungunya infection causes high levels of IFN-α, suggesting strong innate immunity, along with the production of IL-4, IL-10, and IFN-γ, suggesting the engagement of the adaptive immunity. Notably, circulating T lymphocytes showed a CD8+ T lymphocyte response in the early stages of the disease and a CD4+ T lymphocyte-mediated response in the later stages, and IFN-γ and IL-12 levels have been observed to rise dramatically during the acute phase of chikungunya fever. The level of IL-12 returns to normalcy in patients who recover. In contrast, patients who develop chronic arthritis show persistently high IL-12 levels. Histologic examination of synovia from patients with chronic arthritis following chikungunya fever has revealed joint inflammation due to macrophages containing viral material. Elevated expression of MCP-1, MCP-2, and MCP-3 has been associated with bone reabsorption and bone lose, and CHIKV seems to favor a pro-osteoclastic microenvironment disrupting the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio [43,48].
Support cells of the central nervous system, such as astrocytes and oligodendrocytes, have shown to be infected with CHIKV in human, primate, and mice models [49,50]. Apparently, the astrocytes play an important role in replicating the virus and are susceptible to die because of the infection, whereas the microglia seems to be infection-resistant . The infected cells are induced to express high levels of cytokines and chemokines related to an upregulation on innate immune response [50,51]. The adaptive immune response apparently occurs early in the infection. Higher and early increase of IgG3 titers has been correlated with efficient viral clearance and long-term viral protection , whereas higher level of C-reactive protein is related to lymphopenia, lower monocyte level, neutrophilia, and high viral load [19,53].
4. Clinical manifestations and chronic sequelae
It was previously believed that asymptomatic seroconversion was a rare event. However, results point that the subclinical: symptomatic proportion is at least of 4.6:1 patients . The clinical course of CHIK could be divided into three phases: acute, subacute, and chronic. The acute phase has usually been considered from the start of the symptoms (day 0) until the day 10. The most frequent symptoms are arthralgia, fever, and rash [28,55,56]. Other symptoms that could be present are headache, myalgia, pruritus, dizziness, nausea, vomiting, diarrhea, asthenia, red eyes, and although unusual, hemorrhagic symptoms could be present too . The arthralgia usually is a bilateral and symmetric polyarthralgia of large joints that involves the appendicular skeleton; it is more severe in viremic patients, and the joints more frequently affected are of the lower limbs particularly, knees and ankles. Impairment of the finger joints is more frequent in women like the periarticular swelling too. Some patients can feel pain in previous bone fractures or ligament injuries as well as pain along ligament insertions and talalgia [57,58]. Likewise, skin involvement is important, although some studies reporting cutaneous manifestations are limited by the lack of confirmation of infection through serological test. Dermatological lesions comprise a wide spectrum. It could be morbilliform eruption, the most common type of lesion, scaling, confluent macular erythema, intertrigo, hypermelanosis, xerosis, excoriated papules, urticaria, petechial spots, and bullae, among others [58,59]. The macular erythematous rash could appear at fourth day of fever, while dengue rash appears between days 5 and 6, and in Zika fever it could appear on the first symptomatic day. Mucosal involvement has been reported, with aphthous ulcers in mouth, conjunctival injection, and nasal ulceration with nasal skin necrosis [60,61]. Similarly, CHIK cases could manifest with vasculitis in legs or nose with complications that could lead to amputation. Laboratory findings are often unremarkable; lymphopenia and thrombocytopenia could be present but are rare and slight elevation of hepatic aminotransferases could be observed . During this time, there is a lot of overlap between symptoms caused by CHIK, dengue, and Zika, and for this reason differential diagnosis must be made through specific laboratory assessment (Specific IgM titers or RT-PCR) [62,63]. However, some features could help to guide clinical probability in field work. For instance, acute reactants such as C-reactive protein and sedimentation rate could be high, in contrast with dengue and Zika [64–103]. Cardiovascular assessment through electrocardiographic and echocardiographic imaging must be strongly considered. Ventricular and supraventricular arrhythmias and signs of myocarditis or acute effusive pericarditis could be present .
During the acute phase of the disease, some patients evolve to some clinical presentations that, because it is apparent rare occurrence, have been called “atypical manifestations” that include severe disease manifestations. These clinical manifestations include comprises in neurological, respiratory, cardiovascular, and cutaneous systems, among others that could evolve to death [3,61,64–68]. Older age and comorbidities are associated with the appearance of severe cases, death, and evolution to chronic forms of the disease . Ocular manifestations are important too, being the anterior uveitis the most frequent, although retinitis and optic neuritis have also been reported . During the outbreak of 2006 in Reunion Island, mortality attributable to CHIK was recorded, and during the LAC outbreak, fatalities have been noted with an estimated case fatality rate of 0.012% [3,64,65]. It is important to highlight that co-infection could be an issue where co-circulation of CHIK, dengue, and Zika has been reported since mixed clinical pictures could be present.
After 10 days of infection, the majority of patients will improve and symptoms will disappear, but there is a proportion of patients that will evolve to the subacute and chronic phase of the disease. The chronic phase is usually defined as the presence of symptoms at least for 2 or 3 months. The symptoms present during this phase affect quality of life and they can be derived from different involving systems . According with previous estimates, 41.57% of CHIK-infected people would develop chronic inflammatory rheumatism (pCHIK-CIR), both arthritis and arthralgia, at 12 months . Estimates derived from a systematic review and meta-analysis  showed, in the most conservative scenario, about 25% of CHIK would develop pCHIK-CIR, 34% considering the most representative studies, and 14% would develop chronic arthritis. Retrospective studies from cohorts in Colombia support these findings [72,73], but prospective studies are needed in order to establish the real risk of progression in LAC since geographical variation has been reported. When pCHIK-CIR appears, it usually involves ankles, knees, shoulder, and elbow . And sometimes, it can mimic seronegative rheumatoid arthritis [75–77]. Although it is unknown if pCHIK-CIR is a lifetime condition, follow-up studies have found persistence of bone erosions and articular symptoms even after 6 years . The risk of articular symptoms’ persistence is apparently increased with older age, severity of initial joint pain, underlying osteoarthritis, gender (i.e. women), and number of comorbidities [64,70,79–81].
Although less well documented, there are other chronic worrisome sequelae that could be derived from CHIK. For example, chronic sequelae derived from post-CHIK Guillain-Barré or post-CHIK neuropsychiatric disorders such as anxiety or depression [66,67,82,83], vision defects from ocular involvement , or congestive heart failure from dilated cardiomyopathy associated with myocarditis . Hence, although CHIK-burden is already worrisome, derived costs, both direct and indirect, are probably underestimations of the real problem. Healthcare systems of the affected areas must be aware of the possible chronic consequences of CHIK infection and efforts for prevention of infection must be done and proper follow-up of infected patients must be granted. The real scope of the problem is still unknown and more research is needed.
5. Treatment and antiviral development
Until today, CHIKV infection during the acute phase is treated with hydration, non–anti-inflammatory antipyretics (acetaminophen), and symptomatic relief through the use of antihistaminic drugs or lotions for pruritus control. When pain does not relief with usual analgesia, general measures such as alternating cycles of 10 minutes of cold and 20 minutes of warm each 8 hours could be used avoiding the prescription of corticoids or nonsteroidal anti-inflammatory drugs. Currently, there are no approved antivirals to treat the infection, but research in the field has been increasing. Some antiviral molecules, which act by blocking virus proteins important for virus replication, have been reported . Polymerase inhibitors, mainly nucleotide, have been tested with difficulty because the core polymerase subunit nsP4, which is shared by other alphaviruses, is inactive on its own [21,85]. However, Faviparir (6-fluoro-3-hydroxy-2-pyrazinecarbox-amide), a nucleotide RNA-base analog inhibitor, is promising because it reduces CHIKV replication, as well as in other alphaviruses, in mice . Likewise, efforts have been made in order to identify pharmacophore features of protease (nsP2) inhibitors . Molecular modeling has been used in the identification of novel and selective inhibitors with one of them having encouraging features . Other drugs, such as ribavirin, interferon, mycophenolic acid, or arbidol, with known antiviral activity against other pathogens have been proved in CHIKV infection and could potentially be used in treatment [85,89]. Equally, other drugs without conventional antiviral activity have been proposed for treatment. For instance, chloroquine has been suggested as a drug with prophylactic and therapeutic effects apparently by impairing endosomal-mediated virus entry during early stages of virus replication . Other anti-parasite agents, such as ivermectin and a benzimidazole-derived drug, have showed effects on replication at early and late stages of infection [91,92]. Doxycycline combined with ribavirin effectively inhibited CHIKV replication and attenuated its infectivity in vivo in animal models . Besides, some plant-derived products, such as green tea components, flavonoids, diterpene esters, and complex plant alkaloids, have showed antiviral activity against CHIKV [85,94–96].
For the chronic phase of the disease, particularly for articular symptoms, there is little high-quality evidence to guide treatment. Recommendations worldwide have suggested treating inflammatory articular symptoms in an early fashion as rheumatoid arthritis, and some disease-modifying antirheumatic drugs, such as hydroxychloroquine and methotrexate, have been proved in pCHIK-CIR appa rently with good results [77,97]. Glucosamine and chondroitin sulfate could be used to treat pain in patients with previous arthrosis, and those patients with neuropathic pain pregabalin could be prescribed. Treatment of other nonarticular pCHIK chronic sequelae have been poorly studied and reported, and there is no a clinical studied and approved drug for pCHIK-CIR risk reduction. Although studies suggest that passive immunization with monoclonal antibodies may help in CHIKV-infected patients who are at risk of severe disease or in neonates born from viremic mothers .
6. Vaccines, disease prevention and control
Although efforts have increased up to this moment, there is no an approved vaccine for CHIK prevention. There are several vaccine strategies proven in CHIK that comprises live attenuated virus, chimeric virus, DNA vaccines, viral vector vaccines, viral subunits, inactivated virus, and virus-like particles. All of them in preclinical phase trials are used in animal models, mainly mice [85,98]. As for other virus diseases, apparently the best choice for anti-CHIKV vaccination is a strategy using an attenuated live virus vaccine, and there are developed candidates. For instance, two mutant virus strains, with large deletions in either the nsP3 gene or in the entire 6K gene, proved to be genetically stable, attenuated, highly immunogenic, and able to confer durable immunity after a single immunization in mice . Neutralizing antibodies recognize the epitopes in the E2 glycoprotein and therefore E2 is another vaccine candidate .
Besides, efforts have been made in order to improve vector control strategies. Implementation research has been conducted in LAC in order to find ways to improve use of prevention tools such as insecticide-treated nets and covers, education, social mobilization, and water storage cleaning [101,102]. The potential to prevent and control not only CHIK, but to dengue and Zika too, encourages to direct efforts in order to grant vector control. Likewise, recent studies have shown that vector co-infection with the bacterium
Pan American Health Organization. Chikungunya Situation in the Americas 2014 [cited 2016 22/02]. Available from: http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=5855&Itemid=40931&lang=en.
Cardona-Ospina JA, Diaz-Quijano FA, Rodríguez-Morales AJ. Burden of chikungunya in Latin American countries: estimates of disability adjusted life years (DALY) lost in 2014 epidemic. Int J Infect Dis. 2015; 38:60-61.
Cardona-Ospina JA, Henao-SanMartin V, Paniz-Mondolfi AE, Rodriguez-Morales AJ. Mortality and fatality due to chikungunya virus infection in Colombia. J Clin Virol. 2015;70:14-15.
Cardona-Ospina JA, Rodriguez-Morales AJ, Villamil-Gómez W. Burden of chikungunya in one coastal department of Colombia (Sucre): estimates of disability adjusted life years (DALY) lost in 2014 epidemic. J Infect Public Health. 2015;8(6):644-646.
Cardona-Ospina JA, Villamil-Gómez WE, Jimenez-Canizales CE, Castañeda-Hernándeza DM, Rodríguez-Morales AJ. Estimating the burden of disease and the economic cost attributable to chikungunya, Colombia, 2014. Trans R Soc Trop Med Hyg. 2015;109(12):793-802.
Jimenez-Canizales CE, Medina-Gaitan DA, Mondragon-Cardona AE, Rodriguez-Morales AJ. Letter to editor: from imported to an endemic disease: impact of chikungunya virus disease in the hospital epidemiology, tolima, Colombia, 2014-2015. Recent Pat Antiinfect Drug Discov. 2015;10(1):64-66.
Rodriguez-Morales AJ, Cardenas-Giraldo EV, Montoya-Arias CP, Guerrero-Matituy EA, Bedoya-Arias JE, Ramirez-Jaramillo V, et al. Mapping chikungunya fever in municipalities of one coastal department of Colombia (Sucre) using geographic information system (GIS) during 2014 outbreak: Implications for travel advice. Travel Med Infect Dis. 2015; 13(3):256-258.
World Health Organization. Chikungunya in the WHO European Region Copenhagen: WHO; 2015 [cited 2016 22/02]. Available from: http://www.euro.who.int/__data/assets/pdf_file/0005/246164/Fact-sheet-Chikungunya-Eng.pdf?ua=1.
World Health Organization. Chikungunya – France 2014 [cited 2016 22/02]. Available from: http://www.who.int/csr/don/23-october-2014-chikungunya/en/.
World Health Organization. Chikungunya – Spain (update) 2015 [cited 2016 22/02]. Available from: http://www.who.int/csr/don/17-september-2015-chikungunya/en/.
World Health Organization. Chikungunya – Senegal 2015 [cited 2016 22/02]. Available from: http://www.who.int/csr/don/14-september-2015-chikungunya/en/.
Pan American Health Organization. Number of reported cases in the countries of Americas (2016) (by weeks). Pan American Health Organization; 2016. p. 1.
Karabatsos N. International catalogue of arthropod-borne viruses. San Antonio (TX): American Society for Tropical Medicine and Hygiene. 1985;3.
Mason PJ, Haddow AJ. An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53; an additional note on chikungunya virus isolations and serum antibodies. Trans R Soc Trop Med Hyg. 1957;51(3):238-240.
Carey DE. Chikungunya and dengue: a case of mistaken identity? J Hist Med Allied Sci. 1971;26(3):243-262.
Powers AM, Brault AC, Tesh RB, Weaver SC. Re-emergence of chikungunya and O'nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships. J Gen Virol. 2000;81(Pt 2):471-479.
Solignat M, Gay B, Higgs S, Briant L, Devaux C. Replication cycle of chikungunya: a re-emerging arbovirus. Virology. 2009;393(2):183-197.
Powers AM, Logue CH. Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus. J Gen Virol. 2007;88(Pt 9):2363-2377.
Deeba F, Islam A, Kazim SN, Naqvi IH, Broor S, Ahmed A, et al. Chikungunya virus: recent advances in epidemiology, host pathogen interaction and vaccine strategies. Pathog Dis. 2016;74(3).
Golubtsov A, Kaariainen L, Caldentey J. Characterization of the cysteine protease domain of Semliki Forest virus replicase protein nsP2 by in vitro mutagenesis. FEBS Lett. 2006;580(5):1502-1508.
Rubach JK, Wasik BR, Rupp JC, Kuhn RJ, Hardy RW, Smith JL. Characterization of purified Sindbis virus nsP4 RNA-dependent RNA polymerase activity in vitro. Virology. 2009;384(1):201-208.
Abere B, Wikan N, Ubol S, Auewarakul P, Paemanee A, Kittisenachai S, et al. Proteomic analysis of chikungunya virus infected microgial cells. PLoS One. 2012;7(4):e34800.
Volk SM, Chen R, Tsetsarkin KA, Adams AP, Garcia TI, Sall AA, et al. Genome-scale phylogenetic analyses of chikungunya virus reveal independent emergences of recent epidemics and various evolutionary rates. J Virol. 2010;84(13):6497-6504.
Santhosh SR, Dash PK, Parida MM, Khan M, Tiwari M, Lakshmana Rao PV. Comparative full genome analysis revealed E1: A226V shift in 2007 Indian chikungunya virus isolates. Virus Res. 2008;135(1):36-41.
Lanciotti RS, Valadere AM. Transcontinental movement of Asian genotype chikungunya virus. Emerg Infect Dis. 2014;20(8):1400-1402.
Lanciotti RS, Lambert AJ. Phylogenetic analysis of chikungunya virus strains circulating in the Western Hemisphere. Am J Trop Med Hyg. 2016.
Gay N, Rousset D, Huc P, Matheus S, Ledrans M, Rosine J, et al. Seroprevalence of Asian lineage chikungunya virus infection on Saint Martin Island, 7 Months After the 2013 Emergence. Am J Trop Med Hyg. 2016;94(2):393-396.
Mattar S, Miranda J, Pinzon H, Tique V, Bolanos A, Aponte J, et al. Outbreak of chikungunya virus in the north Caribbean area of Colombia: clinical presentation and phylogenetic analysis. J Infect Dev Ctries. 2015;9(10):1126-1132.
Wang C, Saborio S, Gresh L, Eswarappa M, Wu D, Fire A, et al. Chikungunya virus sequences across the first epidemic in Nicaragua, 2014-2015. Am J Trop Med Hyg. 2016;94(2):400-403.
Stapleford KA, Moratorio G, Henningsson R, Chen R, Matheus S, Enfissi A, et al. Whole-genome sequencing analysis from the chikungunya virus Caribbean outbreak reveals novel evolutionary genomic elements. PLoS Negl Trop Dis. 2016;10(1):e0004402.
Teixeira MG, Andrade AM, Costa Mda C, Castro JN, Oliveira FL, Goes CS, et al. East/Central/South African genotype chikungunya virus, Brazil, 2014. Emerg Infect Dis. 2015;21(5):906-907.
Gardner J, Rudd PA, Prow NA, Belarbi E, Roques P, Larcher T, et al. Infectious chikungunya virus in the saliva of mice, monkeys and humans. PLoS One. 2015;10(10):e0139481.
Rolph MS, Zaid A, Mahalingam S. Salivary transmission of the chikungunya arbovirus. Trends Microbiol. 2016;24(2):86-87.
Vasani R, Kanhere S, Chaudhari K, Phadke V, Mukherjee P, Gupta S, et al. Congenital chikungunya-A cause of neonatal hyperpigmentation. Pediatr Dermatol. 2015.
Villamil-Gomez W, Alba-Silvera L, Menco-Ramos A, Gonzalez-Vergara A, Molinares-Palacios T, Barrios-Corrales M, et al. Congenital chikungunya virus infection in Sincelejo, Colombia: a case series. J Trop Pediatr. 2015;61(5):386-392.
Fritel X, Rollot O, Gerardin P, Gauzere BA, Bideault J, Lagarde L, et al. Chikungunya virus infection during pregnancy, Reunion, France, 2006. Emerg Infect Dis. 2010;16(3):418-425.
Gerardin P, Samperiz S, Ramful D, Boumahni B, Bintner M, Alessandri JL, et al. Neurocognitive outcome of children exposed to perinatal mother-to-child chikungunya virus infection: the CHIMERE cohort study on Reunion Island. PLoS Negl Trop Dis. 2014;8(7):e2996.
Ekchariyawat P, Hamel R, Bernard E, Wichit S, Surasombatpattana P, Talignani L, et al. Inflammasome signaling pathways exert antiviral effect against chikungunya virus in human dermal fibroblasts. Infect Genet Evol. 2015;32:401-408.
Schilte C, Buckwalter MR, Laird ME, Diamond MS, Schwartz O, Albert ML. Cutting edge: independent roles for IRF-3 and IRF-7 in hematopoietic and nonhematopoietic cells during host response to chikungunya infection. J Immunol. 2012;188(7):2967-2971.
Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. Persistent chronic inflammation and infection by chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol. 2010;184(10):5914-5927.
Couderc T, Chretien F, Schilte C, Disson O, Brigitte M, Guivel-Benhassine F, et al. A mouse model for chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS Pathog. 2008;4(2):e29.
Ozden S, Huerre M, Riviere JP, Coffey LL, Afonso PV, Mouly V, et al. Human muscle satellite cells as targets of chikungunya virus infection. Plos One. 2007;2(6):e527.
Herrero LJ, Taylor A, Wolf S, Mahalingam S. Arthropod-borne arthritides. Best Pract Res Clin Rheumatol.
Labadie K, Larcher T, Joubert C, Mannioui A, Delache B, Brochard P, et al. Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages. J Clin Invest. 2010;120(3):894-906.
Her Z, Malleret B, Chan M, Ong EK, Wong SC, Kwek DJ, et al. Active infection of human blood monocytes by chikungunya virus triggers an innate immune response. J Immunol. 2010;184(10):5903-5913.
Gardner J, Anraku I, Le TT, Larcher T, Major L, Roques P, et al. Chikungunya virus arthritis in adult wild-type mice. J Virol. 2010;84(16):8021-8032.
Poo YS, Nakaya H, Gardner J, Larcher T, Schroder WA, Le TT, et al. CCR2 deficiency promotes exacerbated chronic erosive neutrophil-dominated chikungunya virus arthritis. J Virol. 2014;88(12):6862-6872.
Chen W, Foo SS, Taylor A, Lulla A, Merits A, Hueston L, et al. Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection. J Virol. 2015;89(1):581-593.
Abraham R, Mudaliar P, Padmanabhan A, Sreekumar E. Induction of cytopathogenicity in human glioblastoma cells by chikungunya virus. PLoS One. 2013;8(9):e75854.
Das T, Hoarau JJ, Jaffar Bandjee MC, Maquart M, Gasque P. Multifaceted innate immune responses engaged by astrocytes, microglia and resident dendritic cells against chikungunya neuroinfection. J Gen Virol. 2015;96(Pt 2):294-310.
Inglis FM, Lee KM, Chiu KB, Purcell OM, Didier PJ, Russell-Lodrigue K, et al. Neuropathogenesis of chikungunya infection: astrogliosis and innate immune activation. J Neurovirol. 2015.
Kam YW, Simarmata D, Chow A, Her Z, Teng TS, Ong EK, et al. Early appearance of neutralizing immunoglobulin G3 antibodies is associated with chikungunya virus clearance and long-term clinical protection. J Infect Dis. 2012;205(7):1147-1154.
Chow A, Her Z, Ong EK, Chen JM, Dimatatac F, Kwek DJ, et al. Persistent arthralgia induced by chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis. 2011;203(2):149-157.
Yoon IK, Alera MT, Lago CB, Tac-An IA, Villa D, Fernandez S, et al. High rate of subclinical chikungunya virus infection and association of neutralizing antibody with protection in a prospective cohort in the Philippines. PLoS Negl Trop Dis. 2015;9(5):e0003764.
Dupuis-Maguiraga L, Noret M, Brun S, Le Grand R, Gras G, Roques P. Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia. PLoS Negl Trop Dis. 2012;6(3):e1446.
Nkoghe D, Kassa RF, Caron M, Grard G, Mombo I, Bikie B, et al. Clinical forms of chikungunya in Gabon, 2010. PLoS Negl Trop Dis. 2012;6(2):e1517.
Thiberville SD, Boisson V, Gaudart J, Simon F, Flahault A, de Lamballerie X. Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean. PLoS Negl Trop Dis. 2013;7(1):e2004.
Staikowsky F, Talarmin F, Grivard P, Souab A, Schuffenecker I, Le Roux K, et al. Prospective study of chikungunya virus acute infection in the Island of La Reunion during the 2005-2006 outbreak. PLoS One. 2009;4(10):e7603.
Riyaz N, Riyaz A, Abdul Latheef EN, Anitha PM, Aravindan KP, Nair AS, et al. Cutaneous manifestations of chikungunya during a recent epidemic in Calicut, north Kerala, south India. Indian J Dermatol Venereol Leprol. 2010;76(6):671-676.
Bandyopadhyay D, Ghosh SK. Mucocutaneous features of chikungunya fever: a study from an outbreak in West Bengal, India. Int J Dermatol. 2008;47(11):1148-1152.
Torres JR, Cordova LG, Saravia V, Arvelaez J, Castro JS. Nasal skin necrosis: an unexpected new finding in severe chikungunya fever. Clin Infect Dis. 2015.
Cardona-Ospina JA, Vera-Polania F, Rodriguez-Morales AJ. Chikungunya or not, differential diagnosis and the importance of laboratory confirmation for clinical and epidemiological research: comment on the article by Rosario et al. Clinical Rheumatology. 2016; 35(3): 829-830.
Magurano F, Zammarchi L, Baggieri M, Fortuna C, Farese A, Benedetti E, et al. Chikungunya from the Caribbean: the importance of appropriate laboratory tests to confirm the diagnosis. Vector Borne Zoonotic Dis. 2015;15(4):258-260.
Economopoulou A, Dominguez M, Helynck B, Sissoko D, Wichmann O, Quenel P, et al. Atypical chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Reunion. Epidemiol Infect. 2009;137(4):534-541.
de la Hoz JM, Bayona B, Viloria S, Accini JL, Juan-Vergara HS, Viasus D. Fatal cases of chikungunya virus infection in Colombia: diagnostic and treatment challenges. Journal of Clinical Virology. 2015;69(0):27-29.
Lebrun G, Chadda K, Reboux AH, Martinet O, Gauzere BA. Guillain-Barre syndrome after chikungunya infection. Emerg Infect Dis. 2009;15(3):495-496.
Villamil-Gomez W, Silvera LA, Paez-Castellanos J, Rodriguez-Morales AJ. Guillain-Barre syndrome after chikungunya infection: a case in Colombia. Enferm Infecc Microbiol Clin. 2016;34(2):140-141.
Oehler E, Fournier E, Leparc-Goffart I, Larre P, Cubizolle S, Sookhareea C, et al. Increase in cases of Guillain-Barre syndrome during a chikungunya outbreak, French Polynesia, 2014 to 2015. Euro Surveill. 2015;20(48).
Mahendradas P, Avadhani K, Shetty R. Chikungunya and the eye: a review. J Ophthalmic Inflamm Infect. 2013;3(1):35.
Couturier E, Guillemin F, Mura M, Leon L, Virion JM, Letort MJ, et al. Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. Rheumatology (Oxford). 2012;51(7):1315-1322.
Rodriguez-Morales AJ, Cardona-Ospina JA, Villamil-Gómez W, Paniz-Mondolfi AE. How many patients with post-chikungunya chronic inflammatory rheumatism can we expect in the new endemic areas of Latin America? Rheumatol Int. 2015; 35(12):2091-2094.
Rodriguez-Morales AJ, Villamil-Gomez W, Merlano-Espinosa M, Simone-Kleber L. Post-chikungunya chronic arthralgia: a first retrospective follow-up study of 39 cases in Colombia. Clin Rheumatol. 2016; 35(3):831-832.
Rodríguez-Morales AJ, Calvache-Benavides CE, Giraldo-Gómez J, Hurtado-Hurtado N, Yepes-Echeverri MC, García-Loaiza CJ, et al. Post-chikungunya chronic arthralgia: results from a retrospective follow-up study of 131 cases in Tolima, Colombia. Travel Med Infect Dis. 2016; 14(1):58-59.
Chopra A, Anuradha V, Ghorpade R, Saluja M. Acute chikungunya and persistent musculoskeletal pain following the 2006 Indian epidemic: a 2-year prospective rural community study. Epidemiol Infect. 2012;140(5):842-850.
Essackjee K, Goorah S, Ramchurn SK, Cheeneebash J, Walker-Bone K. Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus. Postgrad Med J. 2013;89(1054):440-447.
Foissac M, Javelle E, Ray S, Guerin B, Simon F. Post-chikungunya rheumatoid arthritis, Saint Martin. Emerg Infect Dis. 2015;21(3):530-532.
Ganu MA, Ganu AS. Post-chikungunya chronic arthritis - Our experience with dmards over two year follow up. J Assoc Physicians India. 2011;59(2):83-86.
Javelle E, Ribera A, Degasne I, Gauzere BA, Marimoutou C, Simon F. Specific management of post-chikungunya rheumatic disorders: a retrospective study of 159 cases in reunion island from 2006-2012. PLoS Negl Trop Dis. 2015;9(3):e0003603.
Gerardin P, Fianu A, Michault A, Mussard C, Boussaid K, Rollot O, et al. Predictors of chikungunya rheumatism: a prognostic survey ancillary to the TELECHIK cohort study. Arthritis Res Ther. 2013;15(1):R9.
Sebastian MR, Lodha R, Kabra SK. Chikungunya infection in children. Indian J Pediatr. 2009;76(2):185-189.
Sissoko D, Malvy D, Ezzedine K, Renault P, Moscetti F, Ledrans M, et al. Post-epidemic chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis. 2009;3(3):e389.
Bhatia MS, Gautam P, Jhanjee A. Psychiatric morbidity in patients with chikungunya fever: first report from India. J Clin Diagn Res. 2015;9(10):Vc01-Vc03.
Wielanek AC, Monredon JD, Amrani ME, Roger JC, Serveaux JP. Guillain-Barre syndrome complicating a chikungunya virus infection. Neurology. 2007;69(22):2105-2107.
Simon F, Paule P, Oliver M. Chikungunya virus-induced myopericarditis: toward an increase of dilated cardiomyopathy in countries with epidemics? Am J Trop Med Hyg. 2008;78(2):212-213.
Ahola T, Courderc T, Ng LF, Hallengard D, Powers A, Lecuit M, et al. Therapeutics and vaccines against chikungunya virus. Vector Borne Zoonotic Dis. 2015;15(4):250-257.
Delang L, Segura Guerrero N, Tas A, Querat G, Pastorino B, Froeyen M, et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J Antimicrob Chemother. 2014;69(10):2770-2784.
Singh Kh D, Kirubakaran P, Nagarajan S, Sakkiah S, Muthusamy K, Velmurgan D, et al. Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of chikungunya virus nsP2 protease. J Mol Model. 2012;18(1):39-51.
Bassetto M, De Burghgraeve T, Delang L, Massarotti A, Coluccia A, Zonta N, et al. Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus. Antiviral Res. 2013;98(1):12-8.
Di Mola A, Peduto A, La Gatta A, Delang L, Pastorino B, Neyts J, et al. Structure-activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication. Bioorg Med Chem. 2014;22(21):6014-6025.
Khan M, Santhosh SR, Tiwari M, Lakshmana Rao PV, Parida M. Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against chikungunya virus in vero cells. J Med Virol. 2010;82(5):817-824.
Mishra P, Kumar A, Mamidi P, Kumar S, Basantray I, Saswat T, et al. Inhibition of chikungunya virus replication by 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea(MBZM-N-IBT). Sci Rep. 2016;6:20122.
Varghese FS, Kaukinen P, Gläsker S, Bespalov M, Hanski L, Wennerberg K, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res. 2016;126:117-124.
Rothan HA, Bahrani H, Mohamed Z, Teoh TC, Shankar EM, Rahman NA, et al. A combination of doxycycline and ribavirin alleviated chikungunya infection. PLoS One. 2015;10(5):e0126360.
Lani R, Hassandarvish P, Chiam CW, Moghaddam E, Chu JJ, Rausalu K, et al. Antiviral activity of silymarin against chikungunya virus. Sci Rep. 2015;5:11421.
Nothias-Scaglia LF, Pannecouque C, Renucci F, Delang L, Neyts J, Roussi F, et al. Antiviral activity of diterpene esters on chikungunya virus and HIV replication. J Nat Prod. 2015;78(6):1277-1283.
Weber C, Sliva K, von Rhein C, Kummerer BM, Schnierle BS. The green tea catechin, epigallocatechin gallate inhibits chikungunya virus infection. Antiviral Res. 2015;113:1-3.
Chopra A, Saluja M, Venugopalan A. Effectiveness of chloroquine and inflammatory cytokine response in patients with early persistent musculoskeletal pain and arthritis following chikungunya virus infection. Arthritis Rheumatol. 2014;66(2):319-326.
Garcia A, Diego L, Judith B. New approaches to chikungunya virus vaccine development. Recent Pat Inflamm Allergy Drug Discov. 2015;9(1):31-37.
Hallengard D, Kakoulidou M, Lulla A, Kummerer BM, Johansson DX, Mutso M, et al. Novel attenuated chikungunya vaccine candidates elicit protective immunity in C57BL/6 mice. J Virol. 2014;88(5):2858-2866.
Brehin AC, Rubrecht L, Navarro-Sanchez ME, Marechal V, Frenkiel MP, Lapalud P, et al. Production and characterization of mouse monoclonal antibodies reactive to chikungunya envelope E2 glycoprotein. Virology. 2008;371(1):185-195.
Caprara A, Lima JW, Peixoto AC, Motta CM, Nobre JM, Sommerfeld J, et al. Entomological impact and social participation in dengue control: a cluster randomized trial in Fortaleza, Brazil. Trans R Soc Trop Med Hyg. 2015;109(2):99-105.
Quintero J, Garcia-Betancourt T, Cortes S, Garcia D, Alcala L, Gonzalez-Uribe C, et al. Effectiveness and feasibility of long-lasting insecticide-treated curtains and water container covers for dengue vector control in Colombia: a cluster randomised trial. Trans R Soc Trop Med Hyg. 2015;109(2):116-125.
Johnson KN. The impact of Wolbachia on virus infection in mosquitoes. Viruses. 2015;7(11):5705-5717.
Villamil-Gómez WE, Ramirez-Vallejo E, Cardona-Ospina JA, Silvera LA, Rodríguez-Morales AJ. Electrocardiographic alterations in patients with chikungunya fever from Sucre, Colombia: A 42-case series. Travel Med Infect Dis. 2016 (accepted, in press # TMAID-D-16-00072R1) doi: 10.1016/j.tmaid.2016.06.004
Rodríguez-Morales AJ, Cardona-Ospina JA, Urbano-Garzón SF, Hurtado-Zapata JS. Prevalence of post-chikungunya chronic inflammatory rheumatism: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2016. Epub Ahead March 25; available online at: http://onlinelibrary.wiley.com/doi/10.1002/acr.22900/abstract